Infection with cytomegalovirus (CMV) is common in humans and is usually asymptomatic. Weller T H. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. II. N Engl J Med. 1971; 285:267-274; Weller T H. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. I. N Engl J Med. 1971; 285:203-214. In immunocompromised hosts, such as transplant recipients and patients with AIDS, CMV infection is associated with significant morbidity and mortality. Griffiths P D, Clark D A, Emery V C. Betaherpesviruses in transplant recipients. J Antimicrob Chemother. 2000; 45(Suppl T3):29-34; Kovacs A, Schluchter M, Easley K, Demmler G, Shearer W, et al. Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med. 1999; 341:77-84. Cytomegalovirus infection also is the most common congenitally-acquired infection and the leading infectious agent causing mental retardation and deafness in congenitally infected children. Demmler G J. Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis. 1991; 13:315-329.
In recent years, CMV has been associated with a variety of syndromes including hypertension, severe pulmonary complications in patients in intensive care-units, and with a specific brain tumor, glioblastoma multiforme. Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009; 13:R68; Limaye A P, Kirby K A, Rubenfeld G D, Leisenring W M, Bulger E M, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008; 300:413-422; Cheng J, Ke Q, Jin Z, Wang H, Kocher O, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009; 5: e1000427; Mitchell D A, Xie W, Schmittling R, Learn C, Friedman A, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008; 10:10-18. Although the exact role of CMV in these syndromes is unclear, CMV replication appears to affect the natural history and outcome of disease processes in immunocompetent individuals, as well.
Despite significant ongoing research effort, no CMV vaccine is approved for universal or targeted use. Available anti-CMV drugs, e.g., ganciclovir (GCV), cidofovir and foscarnet, effectively inhibit virus replication by targeting the viral DNA polymerase. Matthews T, Boehme R. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis. 1988; 10(Suppl 3):S490-S494; Chrisp P, Clissold S P. Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs. 1991; 41:104-129; Neyts J, Snoeck R, Schols D, Balzarini J, De C E. Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). Virology. 1990; 179:41-50.
Use of these drugs, however, is associated with considerable side effects, such as bone marrow toxicity (GCV) and nephrotoxicity (foscarnet and cidofovir). Schreiber A, Harter G, Schubert A, Bunjes D, Mertens T, et al. Antiviral treatment of cytomegalovirus infection and resistant strains. Expert Opin Pharmacother. 2009; 10:191-209; Biron K K. Antiviral drugs for cytomegalovirus diseases. Antiviral Res. 2006; 71:154-163. Oral valganciclovir has good bioavailability and is used in bone marrow and organ transplant recipients for CMV prophylaxis and treatment. Valganciclovir has not been approved yet for the treatment of infants with congenital CMV infection; a phase III clinical trial comparing six weeks to six months of valganciclovir therapy is actively enrolling infants. Preliminary data from this trial reveal that GCV-resistant variants emerge during therapy. Drug resistance also develops during prolonged or repeated treatment in the transplant population. Chou S. Antiviral drug resistance in human cytomegalovirus. Transpl Infect Dis. 1999; 1:105-114. Accordingly, because of the problems associated with currently available anti-CMV compounds, very limited treatment options for congenital CMV infection exist.